非小细胞肺癌患者eml4-alk基因检测及eml4-alk阳性患者临床特征分析
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摘要
目的探讨棘皮动物微管相关蛋白4(eml4)与间变性淋巴瘤激酶(alk)融合基因阳性非小细胞肺癌(NSCLC)患者的检测、临床特征、治疗、预后以及与egfr、kras、braf基因表达情况之间的联系。方法选取190例NSCLC患者石蜡包埋(FFPE)标本,采用免疫组化(IHC)法进行eml4-alk融合基因阳性NSCLC患者(eml4-alk+NSCLC)筛选,对于IHC阳性的标本使用反转录聚合酶链反应(RT-PCR)检测验证。收集整理eml4-alk+NSCLC的临床资料,并对其随访;对所有患者标本采用RT-PCR法进行egfr、kras、braf突变检测。结果190例NSCLC患者中,经IHC筛查及RT-PCR确证,共检出17例eml4-alk+NSCLC,其中手术标本最多,占47.1%(8/17)(χ~2=25.999,P=0.000),<60岁的占76.5%(13/17)(χ~2=5.813,P=0.016)。未显示eml4-alk融合基因与egfr、kras或braf突变同时出现的患者。在手术患者Ⅰ期未显示eml4-alk阳性肺癌,在Ⅱ~Ⅲa期检出8例eml4-alk阳性肺癌,经术后化疗25%(2/8)复发,2年生存率为100%。9例晚期eml4-alk阳性肺癌患者化疗有效率低(4疗程化疗后仅12.5%缓解),已有5例死亡。一线化疗后病情稳定或缓解的患者维持阶段口服克唑替尼的客观缓解率(ORR)与疾病控制率(DCR)分别达50%、100%。多线治疗后进展患者三线口服克唑替尼2个月ORR与DCR仍可达33.3%、66.7%。结论通过IHC筛查及随后RT-PCR可在各种病理标本中有效检出eml4-alk+NSCLC,其临床特征为<60岁的患者多见,而与性别、吸烟史等其他特征无明显关联。能够手术的较早期(Ⅱ~Ⅲa期)eml4-alk+NSCLC,接受术后辅助化疗预后较好;晚期患者一线化疗后病情稳定或缓解患者口服克唑替尼疗效较好。经多线治疗后使用克唑替尼仍然可提高其ORR及DCR,但获益有限。
Objective To explore the detection,clinical features,treatment and prognosis of non-small cell lung cancer(NSCLC) patients with echinoderm microtubule associated protein-like 4-anaplastie lymphoma kinase(eml4-alk) fusion gene positive and to analyze the relationship between the expression on eml4-alk fusion gene and egfr,kras or braf mutation. Methods Immunohistochemical(IHC) method was used to detect eml4-alk fusion gene expression in formalin-fixed and paraffin-embedded(FFPE) specimens of 190 NSCLS patients,and then the IHC-positive specimens were identified by RT-PCR to confirm the gene expression. The clinical data of patients with eml4-alk + NSCLC were collected and followed up. The RT-PCR was utilized to detect the egfr,kras and braf of all the 190 specimens. Results Among the 190 NSCLC patients,17 patients with eml4-alk fusion gene were detected eml4-alk fusion gene. Among them,surgical specimens were the most,accounting for 47. 1%(8/17)(χ~2= 25. 999,P = 0. 000). Less than 60 years of age accounted for 76. 5%(13/17)(χ~2= 5. 813,P = 0. 016). Patients who did not show eml4-alk fusion gene with egfr,kras or braf mutations simultaneously. 8 cases of eml4-alk fusion gene positive patients were detected in stage Ⅱ-Ⅲa,25%(2/8) recurrence after chemotherapy,the 2-year survival rate was 100%. 9 cases of advanced lung cancer patients with eml4-alk fusion gene eml4-alk positive had low efficiency in chemotherapy and 5 patients had already dead. There were 5 patients who achieved stable disease or partial response after first-line chemotherapy used Crizotinib as maintenance treatment. Their ORR and DCR was40% and 80% respectively after they used Crizotinib for 2 months. There were 3 patients who suffered disease progress after multi-line therapies used Crizotinib for 2 months. Their ORR and DCR still can reach 33. 3% and66. 7% respectively. Conclusion eml4-alk fusion gene significantly associates with age,and there is no significant correlation with other characteristics such as gender,smoking history and other characteristic. Crizotinib could increase ORR and DCR after multi-line therapies in NSCLC patients harbor eml4-alk.
Objective To explore the detection,clinical features,treatment and prognosis of non-small cell lung cancer(NSCLC) patients with echinoderm microtubule associated protein-like 4-anaplastie lymphoma kinase(eml4-alk) fusion gene positive and to analyze the relationship between the expression on eml4-alk fusion gene and egfr,kras or braf mutation. Methods Immunohistochemical(IHC) method was used to detect eml4-alk fusion gene expression in formalin-fixed and paraffin-embedded(FFPE) specimens of 190 NSCLS patients,and then the IHC-positive specimens were identified by RT-PCR to confirm the gene expression. The clinical data of patients with eml4-alk + NSCLC were collected and followed up. The RT-PCR was utilized to detect the egfr,kras and braf of all the 190 specimens. Results Among the 190 NSCLC patients,17 patients with eml4-alk fusion gene were detected eml4-alk fusion gene. Among them,surgical specimens were the most,accounting for 47. 1%(8/17)(χ~2= 25. 999,P = 0. 000). Less than 60 years of age accounted for 76. 5%(13/17)(χ~2= 5. 813,P = 0. 016). Patients who did not show eml4-alk fusion gene with egfr,kras or braf mutations simultaneously. 8 cases of eml4-alk fusion gene positive patients were detected in stage Ⅱ-Ⅲa,25%(2/8) recurrence after chemotherapy,the 2-year survival rate was 100%. 9 cases of advanced lung cancer patients with eml4-alk fusion gene eml4-alk positive had low efficiency in chemotherapy and 5 patients had already dead. There were 5 patients who achieved stable disease or partial response after first-line chemotherapy used Crizotinib as maintenance treatment. Their ORR and DCR was40% and 80% respectively after they used Crizotinib for 2 months. There were 3 patients who suffered disease progress after multi-line therapies used Crizotinib for 2 months. Their ORR and DCR still can reach 33. 3% and66. 7% respectively. Conclusion eml4-alk fusion gene significantly associates with age,and there is no significant correlation with other characteristics such as gender,smoking history and other characteristic. Crizotinib could increase ORR and DCR after multi-line therapies in NSCLC patients harbor eml4-alk.
引文
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[2]侯丹阳,邵璐,徐傲,等,免疫组化检测非小细胞肺癌ALK融合基因表达异常[J].临床与实验病理学杂志,2015,31(5):542-7.
[3]Lohse I,Cao P,Ibrahimov E,et al.Abstract A106:BRCA mutation sensitizes pancreatic tumors to treatment with cisplatin[J].Cancer Res,2015,75(13 Suppl):A106.
[4]钟山,张海萍,郑捷,等.非小细胞肺癌患者eml4-alk融合基因检测及其与临床病理特征的关系[J].中华病理学杂志,2013,42(4):252-6.
[5]Camidge D R,Bang Y J,Kwak E L,et al.Activity and safety of crizotinib in patients with alk-positive non-small-cell lung cancer:updated results from a phase 1 study[J].Lancet Oncol,2012,13(10):1011-9.
[6]Doebele R C,Pilling A B,Aisner D L,et al.Mechanisms of resistance to crizotinib in patients with alk gene rearranged non-small cell lung cancer[J].Clin Cancer Res,2012,18(5):1472-82.
[7]Steuer C E,Ramalingam S S.ALK-positive non-small cell lung cancer:mechanisms of resistance and emerging treatment options[J].Cancer,2014,120(16):2392-402.